Tetrahydrocarbazole derivatives and their pharmaceutical use

ABSTRACT

The present invention relates to novel compounds that are useful in the treatment of human papillomaviruses, and also to the methods for the making and use of such compounds.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US2004/018180 filed Jun. 7, 2004, which claims priority from U.S.60/477,972 filed Jun. 12, 2003 and U.S. 60/497,787 filed Aug. 26, 2003.

FIELD OF THE INVENTION

The present invention relates to novel compounds that are useful in thetreatment of human papillomaviruses, and also to the methods for themaking and use of such compounds.

BACKGROUND OF THE INVENTION

Human Papillomaviruses (HPVs) are small nonenveloped DNA virusesinvolved in many conditions and diseases. For example HPVs cause a widevariety of benign and pre-malignant tumors.

HPV is spread by direct contact. HPVs may be divided into twocategories: cutaneous and mucosal. The cutaneous HPVs cause warts onhands and feet, such as common, plantar, filiform, or flat warts. Themucosal HPV types infect the anogenital region and the oral cavity.Approximately 100 different types of HPV have been characterized todate. Approximately 40 HPV types specifically infect the genital andoral mucosa.

Mucosal HPVs are most frequently sexually transmitted and, with anincidence roughly twice that of herpes simplex virus infection, HPVs areconsidered one of the most common sexually transmitted diseases (STDs)throughout the world. Infection with the human papillomavirus (HPV) maynot cause any symptoms and does not always produce visible genitalwarts. When symptoms do develop, they usually occur 2 to 3 months afterinfection with the virus. Symptoms have been known to develop, however,from 3 weeks to many years after infection occurs. As such, HPV may bespread unknowingly.

More than 25 HPV types that are implicated in anogenital diseases arebroadly classified as either low risk or high risk. Low risk HPVs, suchas HPV-6 and HPV-11, are the etiological cause of genital warts(condyloma acuminata). High risk HPVs, such as HPV-16, 18, 31, 33, 35,39, 45, 51, 52, 56, 58, 59, and 68, usually do not produce visiblegenital warts. Rather the high-risk viral types may be identified by DNAtesting. High risk HPVs such as HPV-16 and HPV-18 may be found on Papscreening tests and be related to precancerous cervical cell change,cervical dysplasia, and cervical cancer. In fact, high-risk HPV types,such as 16, 18, 31, 33, and 35, are strongly associated withprecancerous and cancerous changes of the cervix. Most cervical cancers(about 90%) contain one of these high-risk types. High risk HPVinfection creates a lifetime risk of invasive cancer in the range of5-10% for untreated infection.

In addition to cervical cancer, high risk HPVs are associated with anumber of anal and perianal cancers.

Current treatments for genital warts and cervical dysplasia includephysical removal such as cryotherapy, electrosurgery, and surgicalexcision. Currently, there are no effective antiviral treatments for HPVinfection.

SUMMARY OF THE INVENTION

The present invention includes compounds of formula (I):

wherein

-   n is 0, 1, or 2;-   t is 0 or 1;-   X is —NH—, —O—, —R¹⁰—, —OR¹⁰—, —R¹⁰O—, —R¹⁰OR¹⁰—, —NR¹⁰—, —R¹⁰N—,    —R¹⁰NR¹⁰—, R¹⁰S(O)_(m)—, or —R¹⁰S(O)_(m)R¹⁰—;-   Y is —C(O)— or —S(O)_(m)—;-   each R is the same or different and is independently selected from    the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet,    —NHR¹⁰Het, —OR², —OAy, —OHet, —R¹⁰OR², —NR²R³, —NR²Ay, —R¹⁰NR²R³,    —R¹⁰NR²Ay, —R¹⁰C(O)R², —C(O)R², —CO₂R², —R¹⁰CO₂R², —C(O)NR²R³,    —C(O)Ay, —C(O)NR²Ay, —C(O)Het, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR²R³,    —C(S)NR²R³, —R¹⁰C(S)NR²R³, —R¹⁰NHC(NH)NR²R³, —C(NH)NR²R³,    —R¹⁰C(NH)NR²R³, —S(O)₂NR²R³, —S(O)₂NR²Ay, —R¹⁰SO₂NHCOR²,    —R¹⁰SO₂NR²R³, —R¹⁰SO₂R², —S(O)_(m)R², —S(O)_(m)Ay, cyano, nitro, or    azido;-   each R¹ is the same or different and is independently selected from    the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet,    —NHR¹⁰Het, —OR², —OAy, —OHet, —R¹⁰OR², —NR²R³, —NR²Ay, —R¹⁰NR²R³,    —R¹⁰NR²Ay, —R¹⁰C(O)R², —C(O)R², —CO₂R², —R¹⁰CO₂R², —C(O)NR²R³,    —C(O)Ay, —C(O)NR²Ay, —C(O)Het, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR²R³,    —C(S)NR²R³, —R¹⁰C(S)NR²R³, —R¹⁰NHC(NH)NR²R³, —C(NH)NR²R³,    —R¹⁰C(NH)NR²R³, —S(O)₂NR²R³, —S(O)₂NR²Ay, —R¹⁰SO₂NHCOR²,    —R¹⁰SO₂NR²R³, —R¹⁰SO₂R², —S(O)_(m)R², —S(O)_(m)Ay, cyano, nitro, or    azido;-   each m independently is 0, 1, or 2;-   each R¹⁰ is the same or different and is independently selected from    alkylene, cycloalkylene, alkenylene, cycloalkenylene, and    alkynylene;-   p and q are each independently selected from 0, 1, 2, 3, 4, or 5;-   each of R² and R³ are the same or different and are independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w),    and —R¹⁰NR⁴R⁵;-   w is 1-10;-   each of R⁴ and R⁵ are the same or different and are independently    selected from the group consisting of alkyl, cycloalkyl, alkenyl,    cycloalkenyl, and alkynyl;-   Ay represents an aryl group;-   Het represents a 5- or 6-membered heterocyclyl or heteroaryl group;-   ring A is aryl or heteroaryl;-   provided that when the A ring is aryl, t is 0, and Y is SO₂, then p    is not 0; and-   salts, solvates and physiologically functional derivatives thereof.

Preferably, in describing the present invention in more detail, alkyl isC₁-C₆ alkyl, alkoxy is C₁-C₆ alkoxy, haloalkyl is C₁-C₆ haloalkyl,alkylene is C₁-C₆ alkylene, and alkenylene is C₁-C₆ alkenylene.

In one embodiment t is 0 and Y is —C(O)—. In another embodiment t is 0and Y is —S(O)_(m)—.

In one embodiment t is 1, Y is —C(O)—, and X is —NH—, —O—, —R¹⁰—, or—OR¹⁰—. In another embodiment t is 1, Y is —S(O)_(m)—, and X is —NH—,—O—, —R¹⁰—, or —OR¹⁰—.

In one embodiment preferably n is 1.

Preferably p is 1 or more and when p is 1 or more, R is selected fromhalogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², cyano, nitro,or azido. More preferably R is halogen, alkyl, haloalkyl. Morepreferably R is substituted para to the depicted N atom. More preferablyR is halogen. More preferably R is Br or Cl.

Preferably q is one or more and when q is 1 or more, R¹ is selected fromhalogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², Ay, Het,cyano, nitro, or azido. More preferably R¹ is selected from halogen,alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², or cyano. Preferably R²and R³ each are C₁-C₆ alkyl. More preferably R¹ is selected fromhalogen, alkyl, or —OR². More preferably said halogen is fluoro orchloro, said alkyl is methyl, and said —OR² is alkoxy.

In one embodiment preferably the A ring is aryl. Preferably the A ringis phenyl. Further preferably q is 1 or more and R¹ is selected fromhalogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², Ay, Het,cyano, nitro, or azido. More preferably R¹ is selected from halogen,alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², or cyano.

In another embodiment the A ring is heteroaryl. Preferably theheteroaryl is pyridyl. Preferably q is 0 or 1. Preferably when q is 1,then R¹ is is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³,—C(O)R², —CO₂R², Ay, Het, cyano, nitro, or azido. More preferably when qis 1, then R¹ is is selected from halogen, alkyl, haloalkyl, —OR²,—NR²R³, —C(O)R², —CO₂R², or cyano.

In another embodiment, p is 1, R is halogen, n is 1, Y is —C(O)—, t is0, ring A is heteroaryl, and q is 0. Preferably R is chloro or bromo andring A is pyridyl.

One embodiment includes a compound selected from:

One aspect of the present invention includes one or more of:

-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)urea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxy-2-methylphenyl)urea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)urea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-[(1S)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide;-   Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-nitrobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-chlorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide;-   N-(2,3,4,9-Tetrahydro-1H-carbazol-1-yl)benzamide;-   N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)_(p)-methylbenzenesulfonamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl) nicotinamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide;-   N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea;-   N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide;-   N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide;-   N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-imidazole-5-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide;-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide;-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide;    and-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide.

Preferably, another aspect includes one or more of:

-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide;-   Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-chlorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide;-   N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzenesulfonamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)nicotinamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide;-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide;-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide;    and-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide.

More preferably, one aspect includes one or more of:

-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-nitrobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-chlorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-methylbenzenesulfonamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide;-   N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide;-   N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide;-   N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide;-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide;    and-   N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide.

Another embodiment of the present invention includes:

including salts, solvates and pharmaceutically functional derivativeswherein R⁶ is H, alkyl, —OR², —NR²R³, Ay, Het, —C(O)R², —CO₂R²,—CONR²R³, —S(O)_(m)R², or oxo, where the variables are as defined above;and R⁷ is H or alkyl; provided R⁶ and R⁷ are not both H.

One aspect of the present invention includes a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention includes a compound of the presentinvention for use as an active therapeutic substance.

One aspect of the present invention includes a compound of the presentinvention for use in the treatment or prophylaxis of diseases andconditions caused by oncogenic viruses, including adenoviruses,retroviruses, and papovavirus family, including polyoma viruses andpapilloma viruses.

One aspect of the present invention includes a compound of the presentinvention for use in the treatment or prophylaxis of conditions ordisorders due to HPV infection. Particularly the condition or disease iswarts, genital warts, cervical dysplasia, recurrent respiratorypapillomatosis, or cancers associated with papillomavirus infection.More particularly the cancer is anogenital cancers, head and neckcancers, and skin cancers. More particularly the anogenital cancers arecervical, anal and perianal, vulvar, vaginal, and penile cancers; thehead and neck cancers are oral pharyngeal region and esophagus cancers;and the skin cancers are basal cell carcinoma and squamous cellcarcinoma.

Another aspect of the present invention also includes the use of acompound of the present invention in the manufacture of a medicament foruse in the treatment or prophylaxis of oncogenic viruses, includingadenoviruses, retroviruses, and papovavirus family, including polyomaviruses and papilloma viruses.

One aspect of the present invention includes the use of a compound ofthe present invention in the manufacture of a medicament for use in thetreatment or prophylaxis of conditions or disorders due to HPVinfection. Particularly the present invention includes usefulness withregard to warts, genital warts, cervical dysplasia, recurrentrespiratory papillomatosis, or cancers associated with papillomavirusinfection.

One aspect of the present invention includes a method for the treatmentor prophylaxis of oncogenic viruses, including adenoviruses,retroviruses, and papovavirus family, including polyoma viruses andpapilloma viruses comprising the administration of a compound accordingto the present invention.

One aspect of the present invention includes a method for the treatmentor prophylaxis of conditions or disorders due to HPV infectioncomprising the administration of a compound according to the presentinvention. Particularly the condition or disorder is warts, genitalwarts, cervical dysplasia, recurrent respiratory papillomatosis, orcancers associated with papillomavirus infection.

As noted herein, p and q are each independently defined as 0, 1, 2, 3,4, or 5. Notably, as will be appreciated by those skilled in the art,the value(s) of p and/or q should not exceed the substitutable positionson the depicted rings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein the term “alkyl” refers to a straight or branched chainhydrocarbon, preferably having from one to twelve carbon atoms, that maybe optionally substituted, with multiple degrees of substitutionincluded within the present invention. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl, andsubstituted versions thereof.

As used throughout this specification, the preferred number of atoms,such as carbon atoms, will be represented by, for example, the phrase“C_(x-)C_(y) alkyl,” which refers to an alkyl group, as herein defined,containing the specified number of carbon atoms. Similar terminologywill apply for other preferred terms and ranges as well.

As used herein the term “alkenyl” refers to a straight or branched chainaliphatic hydrocarbon containing one or more carbon-to-carbon doublebonds that may be optionally substituted, with multiple degrees ofsubstitution included within the present invention. Examples include,but are not limited to, vinyl, allyl, and the like and substitutedversions thereof.

As used herein the term “alkynyl” refers to a straight or branched chainaliphatic hydrocarbon containing one or more carbon-to-carbon triplebonds that may be optionally substituted, with multiple degrees ofsubstitution included within the present invention. Examples include,but are not limited to, ethynyl and the like and substituted versionsthereof.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms. Alkylene groups as defined herein may optionally besubstituted, with multiple degrees of substitution included within thepresent invention. Examples of “alkylene” as used herein include, butare not limited to, methylene, ethylene, n-propylene, n-butylene, andsubstituted versions thereof.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms, containing one or more carbon-to-carbon double bonds thatmay be optionally substituted, with multiple degrees of substitutionincluded within the present invention. Examples include, but are notlimited to, vinylene, allylene or 2-propenylene, and the like andsubstituted versions thereof.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms, containing one or more carbon-to-carbon triple bonds thatmay be optionally substituted, with multiple degrees of substitutionincluded within the present invention. Examples include, but are notlimited to, ethynylene and the like and substituted versions thereof.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted non-aromatic cyclic hydrocarbon ring, which optionallyincludes an alkylene linker through which the cycloalkyl may beattached, with multiple degrees of substitution included within thepresent invention. Exemplary “cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and substituted versions thereof. As used herein, the term“cycloalkyl” includes an optionally substituted fused polycyclichydrocarbon saturated ring and aromatic ring system, namely polycyclichydrocarbons with less than maximum number of non-cumulative doublebonds, for example where a saturated hydrocarbon ring (such as acyclopentyl ring) is fused with an aromatic ring (herein “aryl,” such asa benzene ring) to form, for example, groups such as indane.

As used herein, the term “cycloalkenyl” refers to an optionallysubstituted non-aromatic cyclic hydrocarbon ring containing one or morecarbon-to-carbon double bonds which optionally includes an alkylenelinker through which the cycloalkenyl may be attached, with multipledegrees of substitution included within the present invention. Exemplary“cycloalkenyl” groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, andsubstituted versions thereof.

As used herein, the term “cycloalkylene” refers to a divalent,optionally substituted non-aromatic cyclic hydrocarbon ring, withmultiple degrees of substitution included within the present invention.Exemplary “cycloalkylene” groups include, but are not limited to,cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene,cycloheptylene, and substituted versions thereof.

As used herein, the term “cycloalkenylene” refers to a divalentoptionally substituted non-aromatic cyclic hydrocarbon ring containingone or more carbon-to-carbon double bonds, with multiple degrees ofsubstitution included within the present invention. Exemplary“cycloalkenylene” groups include, but are not limited to,cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene,cycloheptenylene, and substituted versions thereof.

As used herein, the term “heterocycle” or “heterocyclyl” refers to anoptionally substituted mono- or polycyclic ring system containing one ormore degrees of unsaturation and also containing one or moreheteroatoms. Preferred heteroatoms include N, O, and/or S, includingN-oxides, sulfur oxides, and dioxides. Preferably the ring is three totwelve-membered and is either fully saturated or has one or more degreesof unsaturation. Multiple degrees of substitution are included withinthe present definition. Such rings may be optionally fused to one ormore of another “heterocyclic” ring(s) or cycloalkyl ring(s). Examplesof “heterocyclic” groups include, but are not limited to,tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted fused benzene ring system,for example anthracene, phenanthrene, or naphthalene ring systems.Multiple degrees of substitution are included within the presentdefiniton. Examples of “aryl” groups include, but are not limited to,phenyl, 2-naphthyl, 1-naphthyl, and substituted derivatives thereof.

As used herein, the term “heteroaryl” refers to an optionallysubstituted monocyclic five to seven membered aromatic ring, or to anoptionally substituted fused bicyclic aromatic ring system comprisingtwo of such aromatic rings. These heteroaryl rings contain one or morenitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. Multiple degreesof substitution are included within the present definition. Examples of“heteroaryl” groups used herein include, but should not be limited to,furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline,benzofuran, benzothiophene, indole, indazole, benzimidizolyl,imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, andsubstituted versions thereof.

As used herein the term “halogen” refers to fluorine, chlorine, bromine,or iodine.

As used herein the term “haloalkyl” refers to an alkyl group, as definedherein, that is substituted with at least one halogen. Examples ofbranched or straight chained “haloalkyl” groups useful in the presentinvention include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, and t-butyl substituted independently with one ormore halogens, e.g., fluoro, chloro, bromo, and iodo. The term“haloalkyl” should be interpreted to include such substituents asperfluoroalkyl groups and the like.

As used herein the term “alkoxy” refers to the group —OR^(a), whereR^(a) is alkyl as defined above.

As used herein the term “alkoxycarbonyl” refers to groups such as:

where the R^(a) represents an alkyl group as herein defined.

As used herein the term “aryloxycarbonyl” refers to groups such as:

where the Ay represents an aryl group as herein defined.

As used herein the term “heteroaryloxycarbonyl” refers to groups suchas:

where the Het represents a heteroaryl group as herein defined.

As used herein the term “nitro” refers to the group —NO₂.

As used herein the term “cyano” refers to the group —CN.

As used herein the term “azido” refers to the group —N₃.

As used herein the term “acyl” refers to the group R^(b)C(O)—, whereR^(b) is alkyl, aryl, heteroaryl, or heterocyclyl, as each is definedherein.

As used herein the term “oxo” refers to the group ═O.

Also, as used herein throughout the present specification, the phrase“optionally substituted” or variations thereof denote an optionalsubstitution, including multiple degrees of substitution, with one ormore substitutent group. The phrase should not be interpreted asduplicative of the substitutions herein described and depicted.Exemplary optional substituent groups include acyl; alkyl; alkenyl;alkynyl; alkylsulfonyl; alkoxy; alkoxycarbonyl; cyano; halogen;haloalkyl; hydroxy; nitro; aryl, which may be further substituted withacyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro; heteroaryl, which may be furthersubstituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl,cyano, halogen, haloalkyl, hydroxy, or nitro; arylsulfonyl, which may befurther substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl,alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro;heteroarylsulfonyl, which may be further substituted with acyl, alkoxy,alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl,hydroxy, or nitro; aryloxy, which may be further substituted with acyl,alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro; heteroaryloxy, which may be furthersubstituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl,cyano, halogen, haloalkyl, hydroxy, or nitro; aryloxycarbonyl, which maybe further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl,alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro;heteroaryloxycarbonyl, which may be further substituted with acyl,alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro; or —N(R*)₂; where for each occurrence R*is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylsulfonyl,arylsulfonyl, or heteroarylsulfonyl, where each occurrence of such arylor heteroaryl may be substituted with one or more acyl, alkoxy, alkyl,alkenyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro, orthe two R*s may combine to form a ring, optionally having additionalheteroatoms, optionally having one or more degrees of unsaturation, andoptionally being further substituted with acyl, alkoxy, alkyl, alkenyl,alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro.

The compounds of formulas (I) may crystallize in more than one form, acharacteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of formula (I). Polymorphismgenerally can occur as a response to changes in temperature, pressure,or both. Polymorphism can also result from variations in thecrystallization process. Polymorphs can be distinguished by variousphysical characteristics known in the art such as x-ray diffractionpatterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also includedwithin the scope of the invention are the individual isomers of thecompounds represented by formula (I), as well as any wholly or partiallyequilibrated mixtures thereof. The present invention also includes theindividual isomers of the compounds represented by the formulas above asmixtures with isomers thereof in which one or more chiral centers areinverted.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the compounds of the presentinvention may comprise acid addition salts. Representative salts includeacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, calcium edetate, camsylate, carbonate, clavulanate, citrate,dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate,gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylsulfate, monopotassium maleate, mucate, napsylate,nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, potassium,salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate,tartrate, teoclate, tosylate, triethiodide, trimethylammonium, andvalerate salts. Other salts, which are not pharmaceutically acceptable,may be useful in the preparation of compounds of this invention andthese should be considered to form a further aspect of the invention.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I, or a salt or physiologically functional derivative thereof)and a solvent. Such solvents, for the purpose of the invention, shouldnot interfere with the biological activity of the solute. Non-limitingexamples of suitable solvents include, but are not limited to water,methanol, ethanol, and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Non-limiting examples of suitablepharmaceutically acceptable solvents include water, ethanol, and aceticacid. Most preferably the solvent used is water.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention that, upon administration to a mammal, is capable ofproviding (directly or indirectly) a compound of the present inventionor an active metabolite thereof. Such derivatives, for example, estersand amides, will be clear to those skilled in the art, without undueexperimentation. Reference may be made to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician. The term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function. For use in therapy,therapeutically effective amounts of a compound of formula (I), as wellas salts, solvates, and physiological functional derivatives thereof,may be administered as the raw chemical. Additionally, the activeingredient may be presented as a pharmaceutical composition.

Accordingly, the invention further provides pharmaceutical compositionsthat include effective amounts of compounds of the formula (I) andsalts, solvates, and physiological functional derivatives thereof, andone or more pharmaceutically acceptable carriers, diluents, orexcipients. The compounds of formula (I) and salts, solvates, andphysiologically functional derivatives thereof, are as herein described.The carrier(s), diluent(s) or excipient(s) must be acceptable, in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient of the pharmaceutical composition.

In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a compound of the formula (I) or salts, solvates, andphysiological functional derivatives thereof, with one or morepharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration are all factors to be considered. Thetherapeutically effective amount ultimately should be at the discretionof the attendant physician or veterinarian. Regardless, an effectiveamount of a compound of formula (I) for the treatment of humanssuffering from frailty, generally, should be in the range of 0.1 to 100mg/kg body weight of recipient (mammal) per day. More usually theeffective amount should be in the range of 1 to 10 mg/kg body weight perday. Thus, for a 70 kg adult mammal the actual amount per day wouldusually be from 70 to 700 mg. This amount may be given in a single doseper day or in a number (such as two, three, four, five, or more) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt, solvate, or physiologically functionalderivative thereof, may be determined as a proportion of the effectiveamount of the compound of formula (I) per se. Similar dosages should beappropriate for treatment of the other conditions referred to herein.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the formula (I), depending on the condition being treated,the route of administration, and the age, weight, and condition of thepatient. Preferred unit dosage formulations are those containing a dailydose or sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient. Such pharmaceutical formulations maybe prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s). By way of example, and not meant to limit the invention,with regard to certain conditions and disorders for which the compoundsof the present invention are believed useful certain routes will bepreferable to others. Based upon the physical manifestations that areoften associated with HPV infection, rectal, topical, or vaginal routesof administration may be preferable. As one example, for the treatmentor prophylaxis of cervical dysplasia the preferred route may be avaginal route.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate, or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants useful in these dosage forms include, for example,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove. Optional ingredients include binders such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and salts, solvates, and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

The compounds of formula (I) and salts, solvates, and physiologicallyfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled.

The compounds may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone (PVP),pyran copolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986), incorporated herein by reference as related to such deliverysystems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The compounds of the present invention and their salts, solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents. The compound(s) of formula(I) and the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately, administrationmay occur simultaneously or sequentially, in any order. The amounts ofthe compound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. Theadministration in combination of a compound of formula (I) salts,solvates, or physiologically functional derivatives thereof with othertreatment agents may be in combination by administration concomitantlyin: (1) a unitary pharmaceutical composition including both compounds;or (2) separate pharmaceutical compositions each including one of thecompounds. Alternatively, the combination may be administered separatelyin a sequential manner wherein one treatment agent is administered firstand the other second or vice versa. Such sequential administration maybe close in time or remote in time.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions and, as such, the compounds of thepresent invention may be used in combination with a variety of othersuitable therapeutic agents useful in the treatment or prophylaxis ofthose disorders or conditions. Treatment will depend upon the nature andtype of HPV infection. As discussed briefly above, treatment for wartscan be divided into ablative and medical approaches. The compounds ofthe present invention may be combined with either or both approaches.

Ablative methods include classic surgical excision and destruction byelectrodesiccation, laser, or liquid nitrogen. Thus, the compounds ofthe present invention may be used in conjunction with such methods orupon reoccurrence after such methods. The compounds of the presentinvention may be used in conjunction with ablative methods to reduce thefrequency of reoccurrence.

Alternatively, the present invention may be combined with other medicaltherapies including a variety of cytotoxic or antiviral agents. Forexample, and not meant to limit the invention, the compounds of thepresent invention may be combined with other therapeutic agents such as5-fluorouracil, retinoic acid, podophyllin, podofilox, keratolyticagents such as salicylic acid and/or lactic acid, haptens such asdiphencyprone (DPC), squaric acid dibutyl ester (SADBE) ordinitrochlorobenzene (DNCB), formalin, topical trichloroacetic acid,topical tretinoin, cidofovir, resiquimod and/or cytokines such asinterferon alfa-2b.

One aspect of the present invention is the use of the compounds of thepresent invention for the treatment or prophylaxis of a variety ofdisorders including, but not limited to, diseases and conditions causedby oncogenic viruses, including adenoviruses, retroviruses, andpapovavirus family, including polyoma viruses and papilloma viruses andmore particularly papilloma viral infections. The present inventionincludes administering to a subject in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

More specifically, the present invention includes the treatment orprophylaxis of conditions or diseases associated with papilloma viralinfections. These conditions and diseases include warts (e.g. plantarwarts), genital warts, recurrent respiratory papillomatosis (e.g.,laryngeal papillomas), and cancers associated with papillomavirusinfection. Cancers that have been associated with papillomavirusinfection include anogenital cancers (e.g., cervical, anal and perianal,vulvar, vaginal, penile cancers), head and neck cancers (e.g., oralpharyngeal region, esophagus), and skin cancers (e.g., basal cellcarcinoma, squamous cell carcinoma). The present invention includesadministering to a subject in need thereof a therapeutically effectiveamount of a compound of the present invention or a salt, solvate orphysiologically functional derivative thereof.

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working Examples.

In all of the examples described below, protecting groups for sensitiveor reactive groups are employed where necessary in accordance withgeneral principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of formula (I).

Those skilled in the art will recognize if a stereocenter exists incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers and includes not only racemic compounds butthe individual enantiomers as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as are known in the art. Resolution ofthe final product, an intermediate, or a starting material may beeffected by any suitable method known in the art. See, for example,Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L.N. Mander (Wiley-Interscience, 1994), incorporated by reference withregard to stereochemistry.

EXPERIMENTAL SECTION

Abbreviations:

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, thefollowing abbreviations may be used in the examples and throughout thespecification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); psi (pounds per square inch); M (molar); mM (millimolar);Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (roomtemperature); h (hours); min (minutes); TLC (thin layer chromatography);mp (melting point); RP (reverse phase); Tr (retention time); TEA(trifluoroacetic acid); TEA (triethylamine); THE (tetrahydrofuran); TFAA(trifluoroacetic anhydride); CD3OD (deuterated methanol); CDCl3(deuterated chloroform); DMSO (dimethylsulfoxide); SiO2 (silica); atm(atmosphere); EtOAc (ethyl acetate); CHCl3 (chloroform); HCl(hydrochloric acid); Ac (acetyl); DMF (N ,N-dimethylformamide); Me(methyl); Cs2CO3 (cesium carbonate); EtOH (ethanol); Et (ethyl); tBu(tert-butyl); MeOH (methanol).

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions conducted at room temperature unlessotherwise noted.

¹H-NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), or br (broad).

Mass spectra were obtained on Micromass Platform or ZMD massspectrometers from Micromass Ltd., Altricham, UK, using eitherAtmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI).

Analytical thin layer chromatography was used to verify the purity ofintermediate(s) which could not be isolated or which were too unstablefor full characterization as well as to follow the progress ofreaction(s).

The absolute configuration of compounds were assigned by Ab InitioVibrational Circular Dichroism (VCD) Spectroscopy. The experimental VCDspectrum were acquired in CDCl₃ using a Bomem ChirallRTM VCDspectrometer operating between 2000 and 800 cm⁻¹. The Gaussian 98 Suiteof computational programs was used to calculate model VCD spectrums. Thestereochemical assignments were made by comparing this experimentalspectrum to the VCD spectrum calculated for a model structure with (R)-or (S)-configuration.

Incorporated by reference with regard to such spectroscopy are: J. R.Chesseman, M. J. Frisch, F. J. Devlin and P. J. Stephens, Chem. Phys.Lett. 252 (1996) 211; P. J. Stephens and F. J. Devlin, Chirality 12(2000) 172; and Gaussian 98, Revision A.11.4, M. J. Frisch et al.,Gaussian, Inc., Pittsburgh Pa., 2002.

Compounds of formula (I) wherein variables are as defined above and LVis a leaving group, namely halogen (F, Cl, Br, I), may be convenientlyprepared by the process outlined in Scheme 1 below:

Generally, the process for preparing the compounds of formula (I), whereLV is a leaving group as defined above (all formulas and variables asdefined above) comprises the steps of:

-   a) reacting a compound of formula (II) with ethyl formate;-   b) reacting the compound of formula (III) with diazacompound of    formula (IV);-   c) indolizing the compound of formula (V) to prepare a compound of    formula (VI);-   d) reductive amination of compound of formula (VI) to form compound    of formula (VII); and-   e) forming compounds of formula (I) from compound (VII) by reaction    with compound of formula (VIII); or alternatively-   f) forming compounds of formula (I) where Y is CO and X is NH via    reaction of compound of formula (VII) with compound of formula (IX).

More specifically, a compound of formula (I) wherein all variables areas defined above can be prepared reacting the compound of formula (VII)with a compound of formula (VIII):

The reaction may be carried out by adding compound of formula (VIII) toa compound of formula (VII) in a suitable solvent, optionally in thepresence of base, and optionally with heating. Suitable solvents includetetrahydrofuran, dichloromethane, N,N-dimethylformamide, pyridine,dioxane, diethyl ether, acetonitrile, toluene, and the like. Suitablebases include triethylamine, diisopropylethylamine, pyridine,dimethylaminopyridine, and the like. As will be appreciated by thoseskilled in the art, compounds of formula (VIII) are commerciallyavailable or can be prepared according to literature methods.

Additionally, as will be appreciated by those skilled in the art, acompound of formula (I) where Y is —C(O)— can also be formed by couplingan amine of formula (VII) and an acid of formula (X^(a)). Any set ofstandard coupling conditions as are known to those skilled in the artmay be used for this coupling.

Alternatively, a compound of formula (I) where Y is —CO— and X is —NH—can be formed by the treatment of a compound of formula (VII) with anisocyanate compound of formula (IX) in a suitable solvent, optionallywith heating. Suitable solvents include tetrahydrofuran and the like.Isocyanates of formula (IX) are commercially available or may beprepared by literature methods that are appreciated by those skilled inthe art.

An amine compound of formula (VII) can be formed from a compound offormula (VI). Treatment of a compound of formula (VI) in an inertsolvent with ammonium salt and a reductive agent, optionally withheating, gives an amine of formula (VII). Suitable solvents include butare not limited to, methanol, ethanol, dichloromethane, dichloroethane,and the like. Suitable reductive agents include but are not limited tosodium cyanoborohydride, sodium triacetoxyborohydride, sodiumborohydride, and the like. Suitable ammonium salts include but are notlimited to ammonium acetate, ammonium formate and the like.

An amine of formula (VII) can also be formed by treatment of a compoundof formula (VI) with hydroxylamine, followed by reduction with suitablereductive agents which include, but are not limited to, lithiumaluminium hydride and the like.

Compounds of formula (VI) are prepared in a similar fashion as describedin the literature (J. Med. Chem. 1973, 16, 425 and J. Org. Chem. 1968,32, 1265), herein incorporated by reference to the extent of suchteaching.

A compound of formula (I) can be converted to another compound offormula (I) by methods appreciated by those skilled in the art.

EXAMPLES Example 1 6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one

a) Cyclohexane-1,2-dione (4-chlorophenyl)hydrazone

To a cold (0° C.) solution of 4-chloroaniline (5.6 g, 44 mmol) inconcentrated hydrochloric acid (5 mL) was added sodium nitrite (3.0 g,44 mmol) dissolved in water (10 mL) portionwise over 20 minutes. Themixture was stirred at 0° C. for 30 minutes. In a separate flask, a coolsolution of 2-(hydroxymethylene)cyclohexanone (Organic Syntheses,Collective Vol 4, 1963, pg. 536) (5.0 g, 40 mmol) in methanol (30 mL)was treated with a solution of sodium acetate (8.3 g, 101 mmol) in water(25 mL). The mixture was stirred at 0° C. for 20 minutes and thediazonium salt slurry was added. The combined mixture was stirred for10-15 minutes, collected by filtration, triturated with ethanol, andcollected by filtration to give cyclohexane-1,2-dione(4-chlorophenyl)hydrazone (4.6 g, 49% yield) as a yellow solid. ¹H-NMR(DMSO-d₆): δ 9.93 (s, 1H), 7.29 (m, 4H), 2.55 (m, 2H), 2.40 (m, 2H),1.84-1.75 (m, 4H).

b) 6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one

A solution of cyclohexane-1,2-dione (4-chlorophenyl)hydrazone (2.3 g,9.7 mmol) in hydrochloric acid (2 mL) and acetic acid (8 mL) was heatedat 120° C. for 20 minutes. The mixture was cooled slightly and treatedwith ice water. The resulting precipitate was collected by filtration togive 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.9 g, 88% yield) asbrown solid. ¹H-NMR (DMSO-d₆): δ 11.78 (s, 1H), 7.75 (m, 1H), 7.38 (d,1H), 7.28 (dd, 1H), 2.92 (t, 2H), 2.55 (t, 2H), 2.13 (q, 2H); MS m/z 220(M+1).

Example 2 6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine

To a solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg,2.3 mmol) and ammonium acetate (1.8 g, 23 mmol) in methanol (9 mL) wasadded sodium cyanoborohydride (720 mg, 11.5 mmol). After heating at 60°C. for 15 hours, the mixture was cooled and treated with concentratedhydrochloric acid until pH=1. The organics were removed under reducedpressure and the resulting precipitate was collected by filtration,dissolved in ethyl acetate and methanol, and washed with saturatedaqueous sodium carbonate. The phases were separated and the organicphase was concentrated to yield6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (260 mg, 52% yield) as alight brown solid. ¹H-NMR (DMSO-d₆): δ 10.90 (s, 1H), 7.34 (m, 1H), 7.27(d, 1H), 6.97 (dd, 1H), 3.90 (t, 1H), 2.54 (m, 2H), 2.04-1.89 (m, 2H),1.66 (m, 1H), 1.50 (m, 1H); MS m/z 221 (M+1).

Example 3 6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one

6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared frombromoaniline and 2-(hydroxymethylene)cyclohexanone in a similar manneras described in Example 1 to give a brown solid. ¹H-NMR (CDCl₃): δ 8.79(s, 1H), 7.80 (s, 1H), 7.44 (d, 1H), 7.30, (d, 1H), 2.97 (t, 2H), 2.66(t, 2H), 2.27 (quint, 2H); MS m/z 265 (M+1).

Example 4 6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine

6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared in a similarmanner as described in Example 2 to give a solid. ¹H-NMR (CDCl₃): δ 8.58(s, 1H), 7.55 (s, 1H), 7.20 (m, 2H), 4.12 (t, 1H), 2.70 (t, 2H), 2.24(m, 1H), 2.05 (m, 1H), 1.92 (m, 3H), 1.66 (m, 1H); MS m/z 266 (M+1).

Example 5 6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one

6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared fromp-toluidine and 2-(hydroxymethylene)cyclohexanone in a similar manner asdescribed in Example 1 to give a tan solid. ¹H-NMR (CDCl₃): δ 8.65 (s,1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 2.98 (t, 2H), 2.65 (t,2H), 2.45 (s, 3H), 2.26 (quint, 2H); MS m/z 220 (M+1).

Example 6 6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine

6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared in asimilar manner as described herein to give a solid. ¹H-NMR (DMSO-d₆): δ10.5 (s, 1H), 7.15 (d, 1H), 7.11 (s, 1H), 6.81 (d, 1H), 3.98 (t, 1H),3.30 (s, 2H), 2.53 (t, 2H), 2.32 (s, 3H), 2.02 (m, 1H), 1.90 (m, 1H),1.68 (m, 1H), 1.65 (m, 1H); MS m/z 201 (M+1).

Example 7 2,3,4,9-Tetrahydro-1H-carbazol-1-one

2,3,4,9-Tetrahydro-1H-carbazol-1-one was prepared from aniline and2-(hydroxymethylene)cyclohexanone in a similar manner as described inExample 1 to give a brown solid. ¹H-NMR (DMSO-d₆): δ 11.6 (s, 1H), 7.66(d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.07 (t, 1H), 2.90 (t, 2H), 2.56(t, 2H), 2.15 (quint, 2H); MS m/z 186 (M+1).

Example 8 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride

To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 8.10 mmol)in ethanol (20 mL) was added a solution of hydroxylamine hydrochloride(1.13 g, 16.2 mmol) in water (10 mL) and a solution of sodium acetate(2.19 g, 26.7 mmol) in water (10 mL). The reaction mixture was heated atreflux for 2 h, cooled, and concentrated. The residue was diluted withwater and extracted with ethyl acetate (2×100 mL). The organic phase wasdried over sodium sulfate, filtered, and concentrated to a brown solid.The oxime was dissolved in THF (80 mL) and lithium aluminum hydride (1.0M in THF, 24.3 mL) was added dropwise. The reaction was heated at refluxfor 7 h and cooled in an ice bath. Methanol was added dropwise untilbubbling ceased. The mixture was diluted with aqueous Na/K tartrate,stirred vigorously for 15 min and extracted with ethyl acetate (2×100mL). The extracts were combined, dried over sodium sulfate, filtered andconcentrated. The crude amine was purified by flash chromatography onsilica (2% to 5% methanol/methylene chloride gradient) to provide2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. The oil wasdiluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. Theresulting precipitate was collected by filtration to provide2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (760 mg, 42%) as alight brown solid. ¹H-NMR (CD₃OD): δ 7.54 (d, 1H), 7.42 (d, 1H), 7.22(t, 1H), 7.09 (t, 1H), 4.66 (t, 1H), 2.95-2.73 (m, 2H), 2.39-2.28 (m,1H), 2.18-2.03 (m, 3H); MS m/z (M+1) 170.

Example 9 N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea

To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg,0.19 mmol) in dichloromethane (1 mL) was added phenyl isocyanate (23 μL,0.21 mmol). The mixture was stirred at room temperature 15 hours and theresulting precipitate collected by filtration to give a gray solid (62%yield). ¹H-NMR (DMSO-d₆): δ 11.01 (s, 1H), 7.60 (d, 1H), 7.45 (m, 2H),7.33-7.23 (m, 4H), 7.17 (dd, 1H), 6.94 (m, 1H), 6.63 (d, 1H), 5.02 (m,1H), 2.68 (m, 2H), 2.06 (m, 1H), 1.95-1.70 (m, 3H); MS m/z 384 (M−1).

Example 10N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)urea

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)ureawas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-methoxyphenyl isocyanate in a similar manner as described above togive a gray solid (61% yield). ¹H-NMR (DMSO-d₆): δ 10.99 (s, 1H), 8.16(s, 1H), 7.60 (d, ₁H), 7.38-7.27 (m, 3H), 7.17 (dd, 1H), 6.87 (d, 2H),6.52 (d, 1H), 5.01 (m, 1H), 3.73 (s, 3H), 2.67 (m, 2H), 2.04 (m, 1H),1.94-1.76 (m, 3H); MS m/z 414 (M−1).

Example 11N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxy-2-methylphenyl)urea

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxy-2-methylphenyl)ureawas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-methoxy-2-methyl isocyanate in a similar manner as described above togive a dark brown solid (59% yield). ¹H-NMR (DMSO-d₆): δ 11.00 (s, 1H),7.71 (d, 1H), 7.60 (d, 1H), 7.47 (s, 1H), 7.32 (d, 1H), 7.17 (dd, 1H),6.88 (d, 1H), 6.75 (m, 2H), 5.00 (m, 1H), 3.73 (s, 3H), 2.69 (m, 2H),2.18 (s, 3H), 2.04 (m, 1H), 1.94-1.77 (m, 3H); MS m/z 430 (M+1).

Example 12N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)urea

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)ureawas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and3-chloro-4-methoxyphenyl isocyanate in a similar manner as describedabove to give a tan solid (42% yield). ¹H-NMR (DMSO-d₆): δ 10.98 (s,1H), 8.33 (s, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 7.25-7.14(m, 2H), 7.08 (d, 1H), 6.63 (d, 1H), 5.01 (m, 1H), 3.82 (s, 3H), 2.65(m, 2H), 2.04 (m, 1H), 1.94-1.76 (m, 3H); MS m/z 448 (M−1).

Example 13N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]ureawas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-dimethylamino phenyl isocyanate in a similar manner as described aboveto give a tan solid (40% yield). ¹H-NMR (DMSO-d₆): δ 10.99 (s, 1H), 7.98(s, 1H), 7.60 (d, 1H), 7.33-7.23 (m, 3H), 7.17 (dd, 1H), 6.71 (d, 2H),6.44 (d, 1H), 5.00 (m, 1H), 2.84 (s, 6H), 2.67 (m, 2H), 2.04 (m, 1H),1.94-1.74 (m, 3H); MS m/z 427 (M−1).

Example 14A N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide

To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg,0.19 mmol) and benzoyl chloride (24 μL, 0.21 mmol) in dichloromethane (1mL) at 0° C. was added diisopropylethylamine (66 μL, 0.38 mmol). Themixture was stirred at room temperature 15 hours, the solvent removed,and the residue purified by flash chromatography (0-30% ethylacetate-hexanes) to give 18 mg (26% yield) of a yellow solid. ¹H-NMR(CDCl₃): δ 8.97 (s, 1H), 7.78 (d, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.44(t, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.42 (d, 1H), 5.34 (m, 1H), 2.72(m, 2H), 2.32 (m, 1H), 2.02-1.93 (m, 3H); MS m/z 369 (M−1).

Example 14BN-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide

Example 14CN-[(1S)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was separatedon a Berger analytical SFC with an HP1100 diode array detector. Thesample was monitored at 230 nm under the following conditions: 30% MeOHin CO₂ with a total flow rate of 2 mL/minute at 2250 psi, 50° C. on aDiacel AD-H column (Chiral Technologies), 4.6×250 mm, 5 μm to giveN-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide (Example14B; retention time=12.37 minutes) andN-[(1S)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide (Example14C; retention time=16.11 minutes). Chirality assigned by VCDspectroscopy.

Example 15N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenylacetyl chloride in a similar manner as described above to give a whitesolid (86% yield). ¹H-NMR (CDCl₃): δ 8.88 (s, 1H), 7.57 (m, 1H),7.37-7.27 (m, 3H), 7.27-7.20 (m, 3H), 7.15 (d, 1H), 5.74 (d, 1H), 5.08(m, 1H), 3.61 (s, 2H), 2.62 (m, 2H), 2.13 (m, 1H), 1.81 (m, 2H), 1.67(m, 1H); MS m/z 383 (M−1).

Example 16N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andhydrocinnamoyl chloride in a similar manner as described above to give awhite solid (53% yield). ¹H-NMR (CDCl₃): δ 8.43 (s, 1H), 7.58 (m, 1H),7.28-7.21 (m, 5H), 7.20-7.15 (m, 2H), 5.51 (d, 1H), 5.05 (m, 1H), 3.00(t, 2H), 2.62 (m, 2H), 2.58-2.43 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H),1.67 (m, 1H); MS m/z 397 (M−1).

Example 17N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamidewas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andcinnamoyl chloride in a similar manner as described above to give anoff-white solid (35% yield).

¹H-NMR (CDCl₃): δ 8.98 (s, 1H), 7.69 (d, 1H), 7.60 (m, 1H), 7.48 (m,2H), 7.36 (m, 3H), 7.22 (dd, 1H), 7.17 (d, 1H), 6.41 (d, 1H), 5.98 (d,1H), 5.25 (m, 1H), 2.68 (m, 2H), 2.26 (m, 1H), 1.99-1.84 (m, 3H); MS m/z395 (M−1).

Example 18 Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate

Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate was preparedfrom 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzylchloroformate in a similar manner as described above to give a whitesolid (16% yield). ¹H-NMR (CDCl₃): δ 8.69 (s, 1H), 7.60 (s, 1H),7.43-7.31 (m, 5H), 7.27-7.21 (m, 1H), 7.17 (d, 1H), 5.16 (q, 2H), 5.08(m, 1H), 4.92 (m, 1H), 2.66 (m, 2H), 2.20 (m, 1H), 1.89 (m, 2H), 1.80(m, 1H); MS m/z 400 (M+1).

Example 19N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamidewas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and2,6-dichlorobenzoyl chloride in a similar manner as described above togive a white solid (25% yield). ¹H-NMR (DMSO-d₆): δ 10.80 (s, 1H), 9.18(d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.36(d, 1H), 7.19 (dd, 1H), 5.27 (m, 1H), 2.69 (m, 2H), 2.08-1.82 (m, 4H);MS m/z 437 (M−1).

Example 20N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-fluorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-fluorobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-fluorobenzoyl chloride in a similar manner as described above to givea white solid (15% yield). ¹H-NMR (DMSO-d₆): δ 11.03 (s, 1H), 8.90 (d,1H), 8.05 (m, 2H), 7.61 (d, 1H), 7.34 (d, 2H), 7.30 (s, 1H), 7.17 (dd,1H), 5.38 (m, 1H), 2.68 (m, 2H), 2.09 (m, 2H), 1.86 (m, 2H); MS m/z 387(M−1).

Example 21 N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andp-anisoyl chloride in a similar manner as described above to give awhite solid (11% yield). ¹H-NMR (DMSO-de): 810.99 (s, 1H), 8.70 (d, 1H),7.96 (d, 2H), 7.60 (d, 1H), 7.29 (d, 1H), 7.16 (dd, 1H), 7.02 (d, 2H),5.38 (m, 1H), 2.67 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H); MS m/z 399(M−1).

Example 22N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-nitrobenzoyl chloride in a similar manner as described above to givean orange solid (32% yield). ¹H-NMR (DMSO-d₆): δ 11.11 (s, 1H), 9.24 (d,1H), 8.36 (d, 2H), 8.19 (d, 2H), 7.62 (m, 1H), 7.29 (d, 1H), 7.18 (dd,1H), 5.41 (m, 1H), 2.69 (m, 2H), 2.10 (m, 2H), 1.89 (m, 2H); MS m/z 414(M−1).

Example 23N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-chlorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-chlorobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-chlorobenzoyl chloride in a similar manner as described above to givea tan solid (69% yield). ¹H-NMR (CDCl₃): δ 8.89 (s, 1H), 7.71 (d, 2H),7.60 (m, 1H), 7.40 (d, 2H), 7.23 (dd, 1H), 7.17 (dd, 1H), 6.36 (d, 1H),5.30 (m, 1H), 2.69 (m, 2H), 2.29 (m, 1H), 1.96 (m, 3H); MS m/z 403(M−1).

Example 24N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andp-toluyl chloride in a similar manner as described above to give ayellow solid (62% yield). ¹H-NMR (CDCl₃): δ 8.97 (s, 1H), 7.67 (d, 2H),7.61 (m, 1H), 7.25-7.20 (m, 3H), 7.17 (d, 1H), 6.36 (d, 1H), 5.30 (m,1H), 2.71 (m, 2H), 2.39 (s, 3H), 2.30 (m, 1H), 1.97 (m, 3H); MS m/z 383(M−1).

Example 25N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamidewas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and4-trifluoromethyl benzoyl chloride in a similar manner as describedabove to give a tan solid (63% yield). ¹H-NMR (CDCl₃): δ 8.83 (s, 1H),7.89 (d, 2H), 7.70 (d, 2H), 7.61 (m, 1H), 7.23 (d, 1H), 7.18 (d, 1H),6.42 (d, 1H), 5.33 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.97 (m, 3H); MSm/z 437 (M−1).

Example 26N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and3-fluorobenzoyl chloride in a similar manner as described above to givea white solid (24% yield). ¹H-NMR (DMSO-d₆): δ 11.04 (s, 1H), 8.97 (d,1H), 7.85-7.81 (m, 1H), 7.81-7.74 (m, 1H), 7.62 (d, 1H), 7.59-7.50 (m,1H), 7.46-7.37 (m, 1H), 7.29 (d, 1H), 7.17 (dd, 1H), 5.38 (m, 1H), 2.68(m, 2H), 2.08 (m, 2H), 1.87 (m, 2H); MS m/z 387 (M−1).

Example 27N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andm-anisoyl chloride in a similar manner as described above to give anorange solid (49% yield). ¹H-NMR (CDCl₃): δ 8.92 (s, 1H), 7.61 (m, 1H),7.38-7.30 (m, 2H), 7.30-7.25 (m, 1H), 7.23 (m, 1H), 7.17 (d, 1H),7.08-7.02 (m, 1H), 6.39 (d, 1H), 5.32 (m, 1H), 3.85 (s, 3H), 2.72 (m,2H), 2.31 (m, 1H), 1.97 (m, 3H); MS m/z 399 (M−1).

Example 28N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andm-toluoyl chloride in a similar manner as described above to give a tansolid (51% yield). ¹H-NMR (CDCl₃): δ 8.95 (s, 1H), 7.63-7.59 (m, 2H),7.55 (m, 1H), 7.33 (m, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.38 (d, 1H),5.32 (m, 1H), 2.72 (m, 2H), 2.40 (s, 3H), 2.31 (m, 1H), 1.98 (m, 3H); MSm/z 383 (M−1).

Example 29N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and2-fluorobenzoyl chloride in a similar manner as described above to givea yellow solid (57% yield). ¹H-NMR (CDCl₃): δ 8.91 (s, 1H), 8.15 (m,1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.23 (dd, 1H), 7.18 (d,1H), 7.12 (m, 2H), 5.35 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m,3H); MS m/z 387 (M−1).

Example 30N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine ando-anisoyl chloride in a similar manner as described above to give a paleorange solid (67% yield). ¹H-NMR (CDCl₃): δ 9.06 (s, 1H), 8.31 (d, 1H),8.25 (dd, 1H), 7.60 (d, 1H), 7.46 (m, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H),7.10 (m, 1H), 6.96 (d, 1H), 5.31 (m, 1H), 3.91 (s, 3H), 2.72 (m, 2H),2.31 (m, 1H), 1.98 (m, 3H); MS m/z 399 (M−1).

Example 31N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and2-nitrobenzoyl chloride in a similar manner as described above to givean orange solid (39% yield). ¹H-NMR (CDCl₃): δ 8.73 (s, 1H), 8.08 (m,1H), 7.68 (m, 1H), 7.60 (m, 2H), 7.54 (m, 1H), 7.29-7.21 (m, 2H), 6.15(d, 1H), 5.42 (m, 1H), 2.69 (m, 2H), 2.33 (m, 1H), 1.96 (m, 3H); MS m/z414 (M−1).

Example 32N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and2-chlorobenzoyl chloride in a similar manner as described above to givea white solid (30% yield). ¹H-NMR (DMSO-d₆): δ 10.98 (s, 1H), 8.89 (d,1H), 7.54 (dd, 2H), 7.48-7.44 (m, 1H), 7.42 (dd, 1H), 7.40-7.34 (m, 1H),7.28 (d, 1H), 7.13 (dd, 1H), 5.26 (m, 1H), 2.60 (m, 2H), 2.08-1.91 (m,2H), 1.90-1.73 (m, 2H); MS m/z 403 (M−1).

Example 33N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine ando-toluoyl chloride in a similar manner as described above to give a graysolid (19% yield). ¹H-NMR (DMSO-d₆): δ 11.01 (s, 1H), 8.70 (d, 1H), 7.59(m, 1H), 7.47 (d, 1H), 7.33 (m, 2H), 7.26 (m, 2H), 7.17 (dd, 1H), 5.34(m, 1H), 2.65 (m, 2H), 2.42 (s, 3H), 2.07 (m, 2H), 1.87 (m, 2H); MS m/z383 (M−1).

Example 34 N-(2,3,4,9-Tetrahydro-1H-carbazol-1-yl)benzamide

N-(2,3,4,9-Tetrahydro-1H-carbazol-1-yl)benzamide was prepared from2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride and benzoylchloride in a similar manner as described above to give a pale yellowsolid (73% yield). ¹H-NMR (CDCl₃): δ 8.79 (s, 1H), 7.81-7.75 (m, 2H),7.54-7.48 (m, 2H), 7.47-7.40 (m, 2H), 7.32 (d, 1H), 7.17 (m, 1H), 7.09(d, 1H), 6.42 (d, 1H), 5.37 (m, 1H), 2.78 (m, 2H), 2.32 (m, 1H),2.03-1.91 (m, 3H); MS m/z 289 (M−1).

Example 35 N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide

N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was preparedfrom 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoylchloride in a similar manner as described above to give a pale yellowsolid (81% yield). ¹H-NMR (CDCl₃): δ 8.63 (s, 1H), 7.81-7.75 (m, 2H),7.54-7.48 (m, 1H), 7.47-7.40 (m, 2H), 7.28 (m, 1H), 7.20 (d, 1H), 6.99(dd, 1H), 6.40 (d, 1H), 5.36 (m, 1H), 2.75 (m, 2H), 2.44 (s, 3H), 2.31(m, 1H), 2.02-1.91 (m, 3H); MS m/z 303 (M−1).

Example 36A N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was preparedfrom 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoylchloride in a similar manner as described above to give a pale yellowsolid (81% yield). ¹H-NMR (CDCl₃): δ 9.02 (s, 1H), 7.79-7.73 (m, 2H),7.54-7.48 (m, 1H), 7.46-7.39 (m, 3H), 7.21 (d, 1H), 7.10 (dd, 1H), 6.45(d, 1H), 5.32 (m, 1H), 2.72 (m, 2H), 2.30 (m, 1H), 2.01-1.90 (m, 3H); MSm/z 323 (M−1).

Example 36BN-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide

Example 36CN-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was separatedon a Berger analytical SFC with an HP1100 diode array detector. Thesample was monitored at 230 nm under the following conditions: 30% MeOHin CO₂ with a total flow rate of 2 mL/minute at 1500 psi, 40° C. on aDiacel AS-H column (Chiral Technologies), 4.6×250 mm, 5 μm to giveR-N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide (retentiontime=5.08 minutes) andS-N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide (retentiontime=7.45 minutes). Chirality assigned by VCD spectroscopy.

Example 37N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzenesulfonamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-methylbenzenesulfonamidewas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andp-toluene sulfonyl chloride in a similar manner as described above togive a tan solid (60% yield). ¹H-NMR (CDCl₃): δ 8.63 (s, 1H), 7.85 (d,2H), 7.57 (m, 1H), 7.37 (d, 2H), 7.25 (m, 1H), 7.18 (d, 1H), 4.74 (d,1H), 4.46 (m, 1H), 2.61 (m, 2H), 2.48 (s, 3H), 2.00-1.82 (m, 2H),1.80-1.60 (m, 2H); MS m/z 419 (M−1).

Example 38N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamidewas prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andpicolinoyl chloride in a similar manner as described above to give anoff-white solid (64% yield). ¹H-NMR (CDCl₃): δ 8.96 (s, 1H), 8.52 (m,1H), 8.37 (d, 1H), 8.21 (m, 1H), 7.86 (m, 1H), 7.61 (m, 1H), 7.43 (m,1H), 7.22 (dd, 1H), 7.17 (d, 1H), 5.31 (m, 1H), 2.72 (m, 2H), 2.31 (m,1H), 1.98 (m, 3H); MS m/z 370 (M−1).

Example 39 N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)nicotinamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)nicotinamide was preparedfrom 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and nicotinylchloride in a similar manner as described above to give a white solid(54% yield). ¹H-NMR (DMSO-d₆): δ 11.02 (s, 1H), 9.08-9.00 (m, 2H), 8.69(dd, 1H), 8.25 (m, 1H), 7.57 (d, 1H), 7.53-7.43 (m, 1H), 7.24 (d, 1H),7.13 (dd, 1H), 5.35 (m, 1H), 2.64 (m, 2H), 2.04 (m, 2H), 1.84 (m, 2H);MS m/z 370 (M−1).

Example 40N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and6-chloronicotinyl chloride in a similar manner as described above togive a white solid (48% yield). ¹H-NMR (DMSO-d₆): δ 11.04 (s, 1H), 9.12(d, 1H), 8.88 (dd, 1H), 8.30 (dd, 1H), 7.64 (dd, 1H), 7.57 (d, 1H), 7.24(m, 1H), 7.13 (dd, 1H), 5.34 (m, 1H), 2.63 (m, 2H), 2.04 (m, 2H), 1.82(m, 2H); MS m/z 404 (M−1).

Example 41N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide

N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide wasprepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine andisonicotinyl chloride in a similar manner as described above to give awhite solid (30% yield). ¹H-NMR (DMSO-d₆): δ 11.04 (s, 1H), 9.13 (d,1H), 8.71 (m, 2H), 7.82 (m, 2H), 7.57 (d, 1H), 7.24 (d, 1H), 7.13 (dd,1H), 5.35 (m, 1H), 2.64 (m, 2H), 2.04 (m, 2H), 1.84 (m, 2H); MS m/z 370(M−1).

Example 42 N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea

N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea was prepared from2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride and phenylisocyanate in a similar manner as described above to give a white solid(60% yield). ¹H-NMR (DMSO-d₆): δ 10.72 (s, 1H), 8.28 (s, 1H), 7.43-7.33(m, 3H), 7.29-7.17 (m, 3H), 7.00 (m, 1H), 6.94-6.83 (m, 2H), 6.52 (d,1H), 4.95 (m, 1H), 2.62 (m, 2H), 1.99 (m, 1H), 1.88-1.70 (m, 3H); MS m/z304 (M−1).

Example 43N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea

N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea wasprepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenylisocyanate in a similar manner as described above to give a white solid(82% yield). ¹H-NMR (DMSO-d₆): δ 10.57 (s, 1H), 8.27 (s, 1H), 7.42-7.34(m, 2H), 7.20 (m, 2H), 7.17-7.11 (m, 2H), 6.87 (m, 1H), 6.82 (m, 1H),6.51 (d, 1H), 4.92 (m, 1H), 2.58 (m, 2H), 2.32 (s, 3H), 1.97 (m, 1H),1.87-1.70 (m, 3H); MS m/z 318 (M−1).

Example 44N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea wasprepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenylisocyanate in a similar manner as described above to give a white solid(74% yield). ¹H-NMR (DMSO-d₆): δ 10.93 (s, 1H), 8.30 (s, 1H), 7.41-7.36(m, 3H), 7.28 (d, 1H), 7.21 (m, 2H), 7.00 (dd, 1H), 6.88 (m, 1H), 6.57(d, 1H), 4.95 (m, 1H), 2.59 (m, 2H), 1.98 (m, 1H), 1.88-1.70 (m, 3H); MSm/z 338 (M−1).

Example 45AN-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamidewas prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine andpicolinoyl chloride in a similar manner as described in Example 14 togive an off-white solid (62% yield). ¹H-NMR (DMSO-d₆): δ 10.93 (s, 1H),8.78 (d, 1H), 8.61 (m, 1H), 8.12 (m, 1H), 8.02 (m, 1H), 7.61 (m, 1H),7.43 (m, 1H), 7.26 (d, 1H), 7.01 (dd, 1H), 5.34 (m, 1H), 2.64 (m, 2H),2.00 (m, 3H), 1.82 (m, 1H); MS m/z 348 (M+Na).

Example 45BN-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamidewas separated on a Berger analytical SFC with an HP1100 diode arraydetector. The sample was monitored at 230 nm under the followingconditions: 30% MeOH in CO₂ with a total flow rate of 2 mL/minute at1500 psi, 40° C. on a Diacel AS-H column (Chiral Technologies), 4.6×250mm, 5 μm to giveN-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide(retention time=4.55 minutes); [α]_(D)=+86; R configuration confirmed byVCD and X-ray crystallography; ¹H-NMR and MS identical to racemiccompound; ¹³C-NMR (DMSO-d₆): δ 164.1, 150.6, 149.1, 138.4, 136.4, 135.3,128.5, 127.2, 123.7, 122.7, 121.5, 117.8, 113.4, 111.2, 44.0, 30.8,21.5, 21.0; HR MS m/z 348.0876 (M+Na); Analytical Calculated forC₁₈H₁₆ClN₃O with ¼H₂O: C, 65.45; H, 5.04; N, 12.72. Found: C, 65.67; H,4.91; N, 12.66. LC-UV purity check: Waters analytical LC-UV consistingof a Waters 626 pumping system, a Waters 996 diode array detector, and aGilson 233XL autosampler; column: Waters Symmetry Shield RP18, 3.9×150mm, 5 m; 50-90% acetonitrile-water (0.1% formic acid); total run time of15 minutes; flow rate remains constant at 1.5 mL/minute; retentiontime=7.41 minutes.

Example 45CN-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamidewas separated on a Berger analytical SFC with an HP1100 diode arraydetector. The sample was monitored at 230 nm under the followingconditions: 30% MeOH in CO₂ with a total flow rate of 2 mL/minute at1500 psi, 40° C. on a Diacel AS-H column (Chiral Technologies), 4.6×250mm, 5 μm to giveN-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide(retention time=6.77 minutes; [α]_(D)=−86); ¹H-NMR and MS identical toracemic compound. Stereochemistry assigned by VCD.

Example 46AN-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide wasprepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and2-fluorobenzoyl chloride in a similar manner as described in Example 14to give a white solid (63% yield). ¹H-NMR (CDCl₃): δ 8.93 (s, 1H), 8.14(m, 1H), 7.49 (m, 1H), 7.45 (m, 1H), 7.28 (m, 1H), 7.22 (d, 1H), 7.10(m, 3H), 5.35 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z343 (M+1).

Example 46BN-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide

Example 46CN-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide wasseparated on a Berger analytical SFC with an HP1100 diode arraydetector. The sample was monitored at 254 nm under the followingconditions: 30% MeOH in CO₂ with a total flow rate of 2 mL/minute at2250 psi, 40° C. on a Diacel OJ-H column (Chiral Technologies), 4.6×250mm, 5 μm to giveN-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide(retention time=6.29 minutes) andN-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide(retention time=9.32 minutes).

Example 47N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 1-methyl-1H-imidazole-5-carboxylic acid (45 mg, 0.36mmol) in dichloromethane (3.6 mL) was added6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (95 mg, 0.43 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (83 mg, 0.43 mmol), and1-hydroxybenzotriazole (54 mg, 0.40 mmol). After 5 minutes,triethylamine (100 μL, 0.72 mmol) was added and the reaction was stirredat room temperature for 15 hours. The reaction mixture was diluted withdichloromethane, washed with water, 1 N hydrochloric acid, 1 N sodiumhydroxide, brine, dried with magnesium sulfate, filtered, andconcentrated. The residue was purified by preparative chromatography(10-90% acetonitrile-water (0.1% trifluoroacetic acid)) and then dilutedwith ethyl acetate, washed with saturated aqueous sodium bicarbonate,and dried with magnesium sulfate to give 43 mg (36% yield) of a whitesolid. ¹H-NMR (CDCl₃): δ 9.21 (s, 1H), 7.43 (m, 1H), 7.32 (s, 1H), 7.30(s, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 3.81(s, 3H), 2.67 (m, 2H), 2.21 (m, 1H), 1.90 (m, 3H); MS m/z 327 (M−1).

Example 48N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamidewas prepared from 2-methyl-2H-pyrazole-3-carboxylic acid and6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid (30% yield). ¹H-NMR (CDCl₃): δ8.69 (s, 1H), 7.45 (m, 2H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.48 (d, 1H),6.26 (d, 1H), 5.28 (m, 1H), 4.22 (s, 3H), 2.71 (m, 2H), 2.28 (m, 1H),1.95 (m, 3H); MS m/z 327 (M−1).

Example 49N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamidewas prepared from 1-methyl-1H-pyrazole-3-carboxylic acid and6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give an off-white solid (20% yield). ¹H-NMR (CDCl₃):δ 8.95 (s, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 7.22 (d, 1H), 7.07 (dd, 1H),6.80 (m, 1H), 5.30 (m, 1H), 3.88 (s, 3H), 2.71 (m, 2H), 2.27 (m, 1H),1.97 (m, 3H); MS m/z 327 (M−1).

Example 50N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamidewas prepared from 4-imidazole carboxylic acid and6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid (4% yield). ¹H-NMR (CDCl₃): δ 9.19(s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.37 (d, 1H), 7.17(d, 1H), 7.05 (dd, 1H), 6.60 (d, 1H), 5.25 (m, 1H), 2.62 (m, 2H), 2.21(m, 1H), 1.91 (m, 3H); MS m/z 313 (M−1).

Example 51N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide

N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamidewas prepared from 1H-pyrazole-3-carboxylic acid and6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid (16% yield). ¹H-NMR (CD₃OD-d₄): δ7.70 (d, ₁H), 7.37 (d, 1H), 7.22 (d, 1H), 6.99 (dd, 1H), 6.81 (d, 1H),5.37 (m, 1H), 2.70 (m, 2H), 2.19 (m, 1H), 2.00 (m, 3H); MS m/z 313(M−1).

Example 52N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide

N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamidewas prepared from 2,6-difluorobenzoylchloride and6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid: ¹H-NMR (CDCl₃): δ 8.80 (s, 1H),7.60 (m, 1H), 7.35 (m, 1H), 7.23 (overlapped dd and d, 2H), 6.94 (t,2H), 6.37 (d, 1H), 5.35 (m, 1H), 2.7 (m, 2H), 2.26 (m, 1H), 1.95 (m,3H); MS m/z 404 (M−1).

Example 53N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide

N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamidewas prepared from 2-fluorobenzenesulfonylchloride and6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid: ¹H-NMR (CDCl₃): δ 8.56 (s, 1H),8.00 (m, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.2-7.4 (m, 3H), 5.04 (d, 1H),4.60 (m, 1H), 2.65 (m, 2H), 1.6-2.1 (m, 4H); MS m/z 421 (M−1).

Example 54N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide

N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamidewas prepared from 2,6-difluorobenzenesulfonylchloride and6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner asdescribed above to give a white solid: ¹H-NMR (CDCl₃): δ 8.60 (s, 1H),7.48-7.58 (m, 2H), 7.24 (dd, 1H), 7.18 (d, 1H), 7.04 (t, 1H), 5.31 (m,1H), 4.73 (m, 1H), 2.62 (m, 2H), 1.7-2.1 (m, 4H).

BIOLOGICAL EXPERIMENTALS AND DATA

Compounds of the current invention are believed useful in the treatmentand/or prophylaxis of conditions and diseases associated with HPVinfection. Activity mediated through HPV was determined using thefollowing W-12 cellular assay.

Cell Culture and Medium

The W12 cell line used contains HPV16 DNA and was derived from alow-grade cervical dysplasia tissue by Margaret Stanley and subsequentlyclonally selected by Paul Lambert (University of Wisconsin). One ofthese clones, W12-20850, contains 1000 copies of episomal HPV16 DNA andwas used in the cell-based assay. W12-20850 cells were routinelycultured with a gamma-irradiated (6000 rads) feeder layer of 3T3 cells.Assays, however, were run in the absence of a 3T3 feeder layer.W12-20850 and 3T3 cells were routinely split when they weresub-confluent. W12-20850 were grown in W12 Medium which is constitutedof 25% DMEM (Gibco BRL, Cat # 12430-047), 75% F12 Media (Gibco BRL, Cat# 11765-021) and 2.5% FBS. The additives include 24.0 mg/ml Adenine(Sigma, Cat # A-9795), 0.4 mg/ml Hydrocortisone (Calbiochem, Cat #386698), 5.0 mg/ml Bovine Insulin (Sigma, Cat # I-1882), 8.4 ng/mlcholera toxin (Fluka, Cat # 26694) and 10 ng/ml EGF (Invitrogen, Cat #13247-051). 3T3 cells were grown in DMEM containing 10% FBS. Cell lineswere incubated at 37° C., in the presence of 5% CO₂.

Cell Based Assay

For the assay, W12-20850 cells were seeded into a 96 wellplate-containing compound. Plates were incubated at 37° C. in thepresence of 5% CO₂, for four days. On the fourth day, cells were lysedand the amount of episomal HPV-16 DNA was quantified using anon-radioactive hybrid capture technique with HPV-16 specific captureand detection probes. The percent inhibition relative to untreatedcontrol cells was then determined.

Hybrid Capture

The hybrid capture assay is run in a 96 well plate format. Hybridizationplates (Nunc Maxisorb Cat # 450320) were coated with a mixture ofcapture probe and ReactiBind solution for at least 4 hours and thenwashed with 0.2)(SSC, 0.05% Tween20 (SSCT) prior to blocking with 150μl/well of 0.2 N NaOH, 1% Igepal, 10 mg/ml hsDNA for 6-8 hours. Thehybridization was carried out by mixing 271 μl of lysed cells with 45 μlof denatured detection probe in 6M guanidine isothiocyanate. To preventevaporation, 50 μl of mineral oil was added to each well. The plate wasthen heated to 90° C. for 6.5 minutes and the hybridization continued at42° C. overnight. Assay plates were washed 6 times with SSC/T.Anti-digoxigenin HRP-conjugated Ab (Boehringer Mannheim 1207733, 1:5000)was incubated in the wells for 30 min at room temperature and washedwith PBS/0.05% Tween-20. SuperSignal LBA substrate (Pierce Cat # 37070)was added, and chemiluminescence was measured using Wallac 1420 Victorplate reader.

Example W-12 (nM)  9 548 10 24000 11 >1000 12 >10000 13 237 14A 32 14B10 14C 5000 15 580 16 1200 17 318 18 44 19 5800 20 20 21 22 22 45 23 1724 8 25 58 26 14 27 28 28 23 29 9 30 >10000 31 >7300 32 1400 33 49734 >10000 35 184 36A 60 36B 20 36C >10000 37 24 38 <10 39 130 40 24 41180 42 >10000 43 >10000 44 1700 45A 10 45B 5 45C 6000 46A 12 46B 746C >3000 47 810 48 2240 49 1650 50 440 51 73 52 45 53 51 54 94

Test compounds were employed in free or salt form.

All research complied with the principles of laboratory animal care (NIHpublication No. 85-23, revised 1985) and GlaxoSmithKline policy onanimal use.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be constructed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

1. A compound of formula (I):

wherein: n is 0, 1, or 2; t is 0 or 1; X is —NH—, —O—, —R¹⁰—, —R¹⁰O—, —R¹⁰OR¹⁰—, —NR¹⁰—, —R¹⁰N—, —R¹⁰NR¹⁰—, —R¹⁰S(O)_(m)—, or —R¹⁰S(O)_(m)R¹⁰—; Y is —S(O)_(m)—; each R is the same or different and is independently selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het, —OR², —OAy, —OHet, —R¹⁰OR², —NR²R³, —NR²Ay, —R¹⁰NR²R³, —R¹⁰NR²Ay, —R¹⁰C(O)R², —C(O)R², —CO₂R², —R¹⁰CO₂R², —C(O)NR²R³, —C(O)Ay, —C(O)NR²Ay, —C(O)Het, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR²R³, —C(S)NR²R³, —R¹⁰C(S)NR²R³, —R¹⁰NHC(NH)NR²R³, —C(NH)NR²R³, —R¹⁰C(NH)NR²R³, —S(O)₂NR²R³, —S(O)₂NR²Ay, —R¹⁰SO₂NHCOR², —R¹⁰SO₂NR²R³, —R¹⁰SO₂R², —S(O)_(m)R², —S(O)_(m)Ay, cyano, nitro, or azido; each R¹ is the same or different and is independently selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het, —OR², —OAy, —OHet, —R¹⁰OR², —NR²R³, —NR²Ay, —R¹⁰NR²R³, —R¹⁰NR²Ay, —R¹⁰C(O)R², —C(O)R², —CO₂R², —R¹⁰CO₂R², —C(O)NR²R³, —C(O)Ay, —C(O)NR²Ay, —C(O)Het, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR²R³, —C(S)NR²R³, —R¹⁰C(S)NR²R³, —R¹⁰NHC(NH)NR²R³, —C(NH)NR²R³, —R¹⁰C(NH)NR²R³, —S(O)₂NR²R³, —S(O)₂NR²Ay, —R¹⁰SO₂NHCOR², —R¹⁰SO₂NR²R³, —R¹⁰SO₂R², —S(O)_(m)R², —S(O)_(m)Ay, cyano, nitro, or azido; each m independently is 0, 1, or 2; each R¹⁰ is the same or different and is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each of R² and R³ are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w), and —R¹⁰NR⁴R⁵; w is 1-10; each of R⁴ and R⁵ are the same or different and are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; Ay represents an aryl group; Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; ring A is aryl or heteroaryl; provided that when the A ring is aryl, t is 0, and Y is SO₂, then p is not 0; or a pharmaceutically acceptable salt or solvate thereof.
 2. The compound of claim 1 wherein alkyl is C₁-C₆ alkyl, alkoxy is C₁-C₆ alkoxy, haloalkyl is C₁-C₆ haloalkyl, alkylene is C₁-C₆ alkylene, and alkenylene is C₁-C₆ alkenylene.
 3. The compound of claim 1 wherein t is 1 and X is —NH—, —O—, or —R¹⁰.
 4. The compound of claim 1 wherein p is 1 or more and R is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², cyano, nitro, or azido.
 5. The compound of claim 4 wherein R is halogen, alkyl, haloalkyl.
 6. The compound of claim 5 wherein R is substituted para to the depicted N atom.
 7. The compound of claim 6 wherein R is halogen.
 8. The compound of claim 7 wherein R is Br or Cl.
 9. The compound of claim 1 wherein q is 1 or more and R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², Ay, Het, cyano, nitro, or azido.
 10. The compound of claim 9 wherein R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², or cyano.
 11. The compound of claim 10 wherein R² and R³ each are C₁-C₆ alkyl.
 12. The compound of claim 10 wherein R¹ is selected from halogen, alkyl, or —OR².
 13. The compound of claim 12 wherein said halogen is fluoro or chloro, said alkyl is methyl, and said —OR² is alkoxy.
 14. The compound of claim 13 wherein q is 1 or more and R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², Ay, Het, cyano, nitro, or azido.
 15. The compound of claim 14 wherein q is 1 or more and R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², or cyano.
 16. The compound of claim 1 wherein the A ring is heteroaryl.
 17. The compound of claim 16 wherein the heteroaryl is pyridyl.
 18. The compound of claim 17 wherein q is 0 or
 1. 19. The compound of claim 18 wherein when q is 1, then R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², Ay, Het, cyano, nitro, or azido.
 20. The compound of claim 19 wherein when q is 1, then R¹ is selected from halogen, alkyl, haloalkyl, —OR², —NR²R³, —C(O)R², —CO₂R², or cyano.
 21. A compound selected from:


22. A compound selected from the group consisting of: N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)urea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxy-2-methylphenyl)urea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(3-chloro-4-methoxyphenyl)urea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-[(1S)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide; Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-dichlorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)₄-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-nitrobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-chlorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide; N-(2,3,4,9-Tetrahydro-1H-carbazol-1-yl)benzamide; N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzenesulfonamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)nicotinamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide; N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea; N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide; N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide; N-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-imidazole-5-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide; N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide; N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide; and N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide.
 23. A compound selected from the group consisting of: N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylprop-2-enamide; Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-nitrobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-chlorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-(trifluoromethyl)benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide; N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzenesulfonamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)nicotinamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)isonicotinamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-imidazole-4-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide; N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide; N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide; and N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide.
 24. A compound selected from the group consisting of: N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-nitrobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-chlorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]benzamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-methylbenzenesulfonamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide; N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-chloronicotinamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide; N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-fluorobenzamide; N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide; and N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide.
 25. A pharmaceutical composition comprising a compound according to any of claims 22 to 24, and a pharmaceutically acceptable carrier.
 26. A method for the treatment of a papovavirus infection selected from the group consisting of polyoma virus infection and papilloma virus infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of claims 22 to
 24. 27. A method for the treatment of conditions or disorders due to HPV infection selected from the group consisting of genital warts and cervical dysplasia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of claims 22 to
 24. 